The serine-threonine kinase AKT (known also as Protein Kinase B) phosphorylates various protein substrates to regulate many key physiological processes, such as cell cycle, glucose metabolism, cell growth and survival, angiogenesis and protein synthesis (Brazil, et al. (2002) Cell 111:293-303). Stimulation of its catalytic activity is triggered by phosphatidylinositol 3 kinase and results from the PtdIns(3,4,5)P-dependent recruitment of AKT, from the cytoplasm to the membrane, as well as the phosphorylation of two regulatory residues, Thr-308 and Ser-473. Phosphorylation of Thr-308, catalyzed by PDK-1, is required for AKT activity, and this activity is augmented, ˜10 fold, by Ser-473 phosphorylation (Alessi, et al. (1996) EMBO J. 15:6541-6551; Brazil, et al. (2002) supra).
Protein Kinase A (PKA) is ubiquitously expressed in mammalian cells and regulates important cellular processes such as growth, development, memory, metabolism, gene expression, and lipolysis. The PKA holoenzyme exists as an inactive complex and is composed of two catalytic (PKAc) and regulatory (PKA RI & RII) subunits. Binding of cAMP facilitates the dissociation and activation of catalytic subunits. Each catalytic subunit is composed of a small and large lobe, with the active site forming a cleft between the two lobes. The small lobe provides the binding site for ATP, and the large lobe provides catalytic residues and a docking surface for peptide/protein substrates. The activation loop in the large lobe contains a phosphorylation site, Thr-197, which is essential for catalysis (Adams, et al. (1995) Biochemistry 34:2447-2454).
Deregulation of AKT signaling pathway is known to be directly associated with some of the most prevalent and incurable human disorders such as cancer, neurodegenerative and psychiatric brain disorders (Blain and Massague (2002) Nat. Med. 8:1076-1078; Brazil, et al. (2004) Trends Biochem. Sci. 29:233-242; Chen, et al. (2003) Cell 113:457-468; Colin, et al. (2005) Eur. J. Neurosci. 21:1478-1488; Emamian, et al. (2004) Nat. Genetics 36:131-137; Griffin, et al. (2005) J. Neurochem. 93:105-117; Liang, et al. (2002) Nat. Med. 8:1153-1160; Shin, et al. (2002) Nat. Med. 8:1145-1152; Viglietto, et al. (2002) Nat. Med. 8:1136-1144). It is well-established that the hyperactivity of AKT is part of the pathologic process in several types of the most prevalent human malignancies (Brazil, et al. (2004) supra), including breast cancer, prostate cancer, lung cancer, gastrointestinal tumors, pancreatic cancer, hepatocellular carcinoma, thyroid cancer, and central nervous system malignancies (such as glioblastoma and gliomas). Association of AKT function with several neurodegenerative brain disorders such as the Alzheimer's disease (AD), Huntington's disease (HD), spinocerebellar ataxia type 1 (SCA1), and amyotrophic lateral sclerosis (ALS), have also been reported (Griffin, et al. (2005) supra; Colin, et al. (2005) supra; Saudou, et al. (1998) Cell 95:55-66; Chen, et al. (2003) supra; Emamian, et al. (2003)Neuron 38:375-387; Kaspar, et al. (2003)Science 301:839-842).
An impairment in the AKT signaling pathway is also involved in schizophrenia (Emamian, et al. (2004) supra). The genetic association of AKT1 gene with schizophrenia has been identified in European (Schwab, et al. (2005) Biol. Psychiatry 58:446-450) and Japanese (Ikeda, et al. (2004) Biol. Psychiatry 56:698-700) populations. Moreover, the PKA signaling pathway has been found to mediate the interaction of DISC1 and PDE4B, genetic factors known to be associated with higher risk for schizophrenia (Millar, et al. (2005) Science 310:1187-1191).
Given the association of AKT with some of the most prevalent and incurable human diseases, including cancer, neurodegenerative and psychiatric disorders, there is a need in the art to identify agents which interact with and modulate the activity of AKT. The present invention meets this need in the art.